Restenosis of the artery lumen following arterial reconstruction remains a major problem in the treatment of atherosclerosis. The mechanisms of artery lumen narrowing following reconstruction are poorly defined. Recent evidence, particularly that from intravascular ultrasound, suggests that the traditional view of restenosis as being due to lumen encroachment from intimal growth is wrong. Rather, it appears that lumen size may be determined by changes in artery wall diameter, or remodeling. Our recent data from a model of angioplasty in atherosclerotic nonhuman primates support this mechanism of lumen narrowing and suggest that failure of the artery wall to remodel and enlarge to accommodate intimal growth, is a central component of restenosis. We propose two hypotheses to explain wall contraction in injured atherosclerotic arteries. First, lumen narrowing may be due to the same kinds of tissue contraction seen during wound healing. Fractures created by angioplasty may contract by an analogous mechanism, an interplay among contractile cells, integrins and the extracellular matrix. Second, the degree to which enzymes important in extracellular matrix degradation (metalloproteinases) are expressed within the injured artery wall may determine the capacity of the wall to remodel. Arteries with decreased metalloproteinase activity may be less capable of remodeling in response to intimal growth, resulting in restenosis. These hypotheses will be explored in atherosclerotic nonhuman primates undergoing angioplasty. We have collected a number of arteries from previous studies of angioplasty in this model. These tissue will be used to extensively characterize structural, histological and biochemical variables associated with lumen narrowing after injury. Changes in lumen size will be compared to expression of integrins, their matrix ligands and metalloproteinases which may play a role in wall remodeling. New animal studies will directly address the mechanism of tissue contraction in remodeling through targeted blocking experiments of integrins. Animals will be treated with a blocking antibody specific for the avbeta3 integrin at the time of angioplasty. Lumen caliber will be assessed by quantitative angiography to determine the degree of lumen narrowing. Histological, morphological and angiographic end points will be measured in these arteries to determine their role in wall remodeling. The effects of integrin-blockade on metalloproteinase expression and activity will be assessed and related to lumen narrowing, as integrin signaling pathways are important in their regulation. These studies will further our understanding of the structural basis of restenosis in atherosclerotic arteries and may identify distinct molecular targets for preventive therapy.